Intermittent exposures to carbon monoxide (CO) concentrations that exceed permissible levels are thought to contribute to the increased incidence of cardiovascular disease in exposed workers. A valid assessment of the cardiac risk associated with these exposures has proved difficult, in part because of limited information regarding the degree of hypoxia that occurs in heart tissue during these exposures. Although the Coburn-Forster-Kane Equation (CFKE) is often used to predict CO uptake by, and removal from, hemoglobin (Hb), it can not estimate CO uptake by extravascular tissues such as muscle, a potentially large storage site for CO as muscle accounts for approximately 41% of body weight in young, adult males. Therefore, we developed, and validated with human data, a mathematical model of CO uptake and washout that, unlike the CFKE, includes a muscle compartment. Our model predicts that the CO concentration in muscle increases soon after the onset of the exposure and rises steadily as carboxyhemoblobin (COHb) increases. When used to assess CO washout under hyperoxia, the common treatment strategy for toxic CO exposures, our model predicts a further rise in CO uptake by muscle myoglobin (Mb), even as COHb levels fall, suggesting an increased risk for hypoxic injury to the myocardium. Based on these results, we hypothesize that a mathematical model that could predict COMb levels in cardiac muscle would provide a more accurate estimate of risk for cardiac hypoxia than COHb alone. Accordingly, the objectives of this proposal are to use data sets obtained from two human CO exposure experiments to: 1) enhance our model to enable it to predict COHb and COMb during exercise and washout under hyperoxia, and 2) evaluate the correlation between the predicted CO dose to the heart and subtle ECG changes during exercise and washout under hyperoxia. To accomplish these objectives we will expand the model to include a separate myocardial compartment, optimize our method for fitting the model and estimating myocardial COMb at rest and during exercise in each subject, and correlate model estimates of myocardial COMb levels with degree of cardiac electrical instability. Relevance: To understand the increased risk for heart disease in workers exposed to carbon monoxide, we will use our mathematical model to analyze existing data from exposed humans to determine the exposure conditions likely to damage the heart. We will also determine whether treatment with 100% oxygen may be harmful in some cases. [unreadable] [unreadable]